MECHANISMS OF NEURONAL CELL-DEATH IN WERNICKES ENCEPHALOPATHY

Wernicke's Encephalopathy (WE) is a serious neurological disorder resu lting from thiamine deficiency, encountered in chronic alcoholics and in patients with grossly impaired nutritional status. Neuropathologic studies as well as Magnetic Resonance Imaging reveal selective diencep halic and brainstem lesions in patients with WE. The last decade has w itnessed major advances in the understanding of pathophysiologic mecha nisms linking thiamine deficiency to the selective brain lesions chara cteristic of WE. Activities of the thiamine-dependent enzyme alpha-ket oglutarate dehydrogenase, a rate-limiting tricarboxylic acid cycle enz yme are significantly reduced in autopsied brain tissue from patients with WE and from rats treated with the central thiamine antagonist, py rithiamine. In the animal studies, evidence suggests that such enzyme deficits result in focal lactic acidosis, cerebral energy impairment a nd depolarization resulting from increased release of glutamate in vul nerable brain structures. It has been proposed that this depolarizatio n may result in N-Methyl-D-Aspartate receptor-mediated excitotoxicity as well as increased expression of immediate early genes such as c-fos and c-jun resulting in apoptotic cell death. Other mechanisms involve d in thiamine deficiency-induced cell loss may involve free radicals a nd alterations of the blood-brain barrier. Additional studies are stil l required to identify the site of the initial cellular insult and to explain the predilection of diencephalic and brainstem structures due to thiamine deficiency.